Focal And Segmental Glomerulosclerosis Patients Research Articles

Podocyte number and glomerulosclerosis indices are associated with the response to therapy for primary focal segmental glomerulosclerosis.

Corticosteroid therapy, often in combination with inhibition of the renin-angiotensin system, is first-line therapy for primary focal and segmental glomerulosclerosis (FSGS) with nephrotic-range proteinuria. However, the response to treatment is variable, and therefore new approaches to indicate the response to therapy are required. Podocyte depletion is a hallmark of early FSGS, and here we investigated whether podocyte number, density and/or size in diagnostic biopsies and/or the degree of glomerulosclerosis could indicate the clinical response to first-line therapy. In this retrospective single center cohort study, 19 participants (13 responders, 6 non-responders) were included. Biopsies obtained at diagnosis were prepared for analysis of podocyte number, density and size using design-based stereology. Renal function and proteinuria were assessed 6 months after therapy commenced. Responders and non-responders had similar levels of proteinuria at the time of biopsy and similar kidney function. Patients who did not respond to treatment at 6 months had a significantly higher percentage of glomeruli with global sclerosis than responders (p < 0.05) and glomerulosclerotic index (p < 0.05). Podocyte number per glomerulus in responders was 279 (203-507; median, IQR), 50% greater than that of non-responders (186, 118-310; p < 0.05). These findings suggest that primary FSGS patients with higher podocyte number per glomerulus and less advanced glomerulosclerosis are more likely to respond to first-line therapy at 6 months. A podocyte number less than approximately 216 per glomerulus, a GSI greater than 1 and percentage global sclerosis greater than approximately 20% are associated with a lack of response to therapy. Larger, prospective studies are warranted to confirm whether these parameters may help inform therapeutic decision making at the time of diagnosis of primary FSGS.

High Rate of Mutations of Adhesion Molecules and Extracellular Matrix Glycoproteins in Patients with Adult-Onset Focal and Segmental Glomerulosclerosis.

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.

Nephrotic syndrome: Current understanding and future therapies

Advances in basic and clinical research have improved ourunderstanding of the pathomechanisms underlying nephrotic syndrome caused by minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS). These advances are reflected in the new 2021 KDIGO-Guidelines, which emphasize the clear distinction between primary, secondary and genetic causes. Proper classification is critical, as it directly affects the therapy of choice. While glucocorticoids still play a central in inducing remission in primary forms, calcineurin inhibitors, mycophenolate mofetil, cyclophosphamide and rituximab (off label) are viable adjuncts/alternatives to reduce or replace glucocorticoids in case of side effects or contraindications. Since SGLT-2-inhibitors have shown renoprotective effects in non-diabetic patients and may help to reduce proteinuria, they should be considered in all (adult) patients with chronic kidney disease, including MCD and FSGS patients. In the near future, Sparsentan, an endothelin type A and angiotensin receptor blocker may be added to the growing arsenal of proteinuria-reducing agents, with a phase 3 trail expected to be completed in late 2022. Finally, we recommend the inclusion of all MCD/FSGS patients in clinical registries (e. g. FOrMe Registry in Germany) to ensure adequate therapy and genetic testing if indicated. In addition, national registries are an invaluable source of clinical data that helps to refine our therapies towards individualized medicine.

Podocyte RNA sequencing reveals Wnt- and ECM-associated genes as central in FSGS.

Loss of podocyte differentiation can cause nephrotic-range proteinuria and Focal and Segmental Glomerulosclerosis (FSGS). As specific therapy is still lacking, FSGS frequently progresses to end-stage renal disease. The exact molecular mechanisms of FSGS and gene expression changes in podocytes are complex and widely unknown as marker changes have mostly been assessed on the glomerular level. To gain a better insight, we isolated podocytes of miR-193a overexpressing mice, which suffer from FSGS due to suppression of the podocyte master regulator Wt1. We characterised the podocytic gene expression changes by RNAseq and identified many novel candidate genes not linked to FSGS so far. This included strong upregulation of the receptor tyrosine kinase EphA6 and a massive dysregulation of circadian genes including the loss of the transcriptional activator Arntl. By comparison with podocyte-specific changes in other FSGS models we found a shared dysregulation of genes associated with the Wnt signaling cascade, while classical podocyte-specific genes appeared widely unaltered. An overlap with gene expression screens from human FSGS patients revealed a strong enrichment in genes associated with extra-cellular matrix (ECM) and metabolism. Our data suggest that FSGS progression might frequently depend on pathways that are often overlooked when considering podocyte homeostasis.

Podocin and uPAR are good biomarkers in cases of Focal and segmental glomerulosclerosis in pediatric renal biopsies.

There are controversies whether Minimal Change Disease (MCD) and Focal and Segmental Glomerulosclerosis (FSGS) are distinct glomerular lesions or different manifestations within the same spectrum of diseases. The uPAR (urokinase-type plasminogen activator receptor) and some slit diaphragm proteins may be altered in FSGS glomeruli and may function as biomarkers of the disease in renal biopsies. Thus, this study aims to evaluate the diagnostic potential of uPAR and glomerular proteins for differentiation between MCD and FSGS in renal pediatric biopsy. Renal biopsies from 50 children between 2 and 18 years old were selected, with diagnosis of MCD (n = 29) and FSGS (n = 21). Control group consisted of pediatric autopsies (n = 15) from patients younger than 18 years old, with no evidences of renal dysfunction. In situ expressions of WT1, nephrin, podocin and uPAR were evaluated by immunoperoxidase technique. Renal biopsy of patients with MCD and FSGS expressed fewer WT1 (p≤0.0001, F = 19.35) and nephrin (p<0.0001; H = 21.54) than patients in the control group. FSGS patients expressed fewer podocin than control (p<0.0359, H = 6.655). FSGS cases expressed more uPAR than each of control and MCD (p = 0.0019; H = 12.57) and there was a positive and significant correlation between nephrin and podocin (p = 0.0026, rS = 0.6502) in these cases. Podocin had sensitivity of 73.3% and specificity of 86.7% (p = 0.0068) and uPAR had sensitivity of 78.9% and specificity of 73.3% (p = 0.0040) for diagnosis of FSGS patients. The main limitation of the study is the limited number of cases due to the difficulty in performing biopsy in pediatric patients. Podocin and uPAR are good markers for FSGS and differentiate these cases from MCD, reinforcing the theory of distinct glomerular diseases. These findings suggest that podocin and uPAR can be used as biomarkers in the routine analysis of renal biopsies in cases of podocytopathies when the lesion (sclerosis) is not sampled.

Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors

Primary forms of focal and segmental glomerulosclerosis (FSGS) are driven by circulating factors that cause dysfunction or loss podocytes. Rare genetic forms of FSGS can be caused by mutations in TRPC6, which encodes a Ca2+-permeable cationic channel expressed in mesangial cells and podocytes; and NPHS2, which encodes podocin, a TRPC6-binding protein expressed in podocyte slit diaphragm domains. Here we observed that exposing immortalized mouse podocytes to serum or plasma from recurrent FSGS patients for 24h increased the steady-state cell-surface abundance of TRPC6, accompanied by an increase in currents through endogenous TRPC6 channels evoked by a hypoosmotic stretch stimulus. These effects were mimicked by the soluble urokinase receptor (suPAR) and by tumor necrosis factor (TNF), circulating factors implicated in nephrotic syndromes. Most but not all of the recurrent FSGS plasma samples that we examined also caused a loss of podocin over a period of several hours. The loss of podocin was also seen following exposure to suPAR but not TNF. However, TNF increased the effects of suPAR on TRPC6 and podocin, and TNF and suPAR are required for the full effects of one of the recurrent FSGS plasma samples. The actions of FSGS plasma, suPAR and TNF on surface abundance of TRPC6 were blocked by cilengitide, an inhibitor of αvβ3-integrin signaling. These data suggest that primary FSGS is a heterogeneous condition mediated by multiple circulating factors, and support TRPC6 and αvβ3-integrin as potential therapeutic targets.

Reassessing the Reassessment of suPAR in Glomerular Disease.

Soluble urokinase receptor (suPAR) is proposed as circulating factor in focal and segmental glomerulosclerosis (FSGS) (1). Spinale et al. attempt to validate the role of suPAR in glomerular disease (2). Their mouse overexpression experiments of physiological suPAR forms are distinct from the studies by Wei et al. that expressed either alternate suPAR forms or used different mouse models (1). Additional experiments will help to further clarify the distinct roles of suPAR variants. Spinale et al. extend previous clinical studies indicating that glomerular filtration rate (GFR) is an important determinant of suPAR (3). This, however, does not imply that suPAR is only bystander, as illustrated by epidemiological studies linking elevated suPAR – independent of the eGFR – to cardiovascular disease in patients with CKD (4). As for most large protein plasma components, the balance between generation and clearance determines suPAR accumulation, adding complexity when studying the direct renal effects of suPAR, especially when possibly also causing kidney disease. Biopsy proven FSGS patients with GFR >40 ml/min have in 50% elevated suPAR levels (5), suggesting also suPAR production. In addition, suPAR fragments (measured and unmeasured) may cause podocyte injury, potentially contributing to a reduced GFR. The strong effect of a low GFR on serum suPAR levels in observational studies could obfuscate the effects of suPAR-induced glomerular pathology. In conclusion, dependence of serum suPAR levels on GFR precludes using suPAR as a single value biomarker for FSGS in conditions of low GFR, but this correlation does not serve as an explanation for elevated suPAR under preserved GFR (Figure ​(Figure11). Figure 1 suPAR plasma levels above cut off of 3000 pg/ml in patients with eGFR >40 ml/min (blue line) as suggested by Li et al. applied to the patient cohort by Spinale et al. These values are likely not explained by reduced GFR alone. ...

Focal and segmental glomerulosclerosis: does prognosis vary with the variants?

Focal and segmental glomerulosclerosis (FSGS) is a clinicopathological entity. The following five FSGS variants: Collapsing, cellular, glomerular tip, peri-hilar and not otherwise specified (NOS) are recognized, which may have prognostic value. The aim of this study was to highlight the clinical course and outcome in the different pathological variants of FSGS and to evaluate the predictive risk factors of end-stage renal disease (ESRD). It was a retrospective analysis of biopsy-proven primary FSGS patients who presented over a period of three years. The data were collected from the clinical and biopsy records of the Nephrology Unit. There were 116 patients with biopsy-proven FSGS. The frequency of occurrence of FSGS among all cases of the nephrotic syndrome seen in our unit was 35.47%. NOS was the most common pathological variant (62.2%), followed by peri-hilar (11.2%), cellular (9.4%) and glomerular tip (7.7%), and the least common variant was collapsing (4.3%). Majority of patients with collapsing, NOS and glomerular tip variants had nephrotic range proteinuria. However, the amount of proteinuria was highest in the glomerular tip and collapsing variants. A higher percentage of patients with the collapsing and cellular variants had renal failure at the time of presentation. A higher rate of tubular and interstitial changes was seen in the collapsing and cellular variants. The collapsing and cellular variants showed lower response rate and higher rates of ESRD, while the glomerular tip lesion had the highest remission rate and the lowest rate of ESRD. Poor prognostic factors for ESRD in FSGS were initial renal insufficiency, severe tubulo-interstitial change, initial nonresponsiveness to steroids and collapsing histopathological variant. Our study suggests that histopathological classification of FSGS is of paramount importance in the management and in predicting the prognosis.

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the renin–angiotensin–aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild-type BALB/c mice after intravenous injection.We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was re-sequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells.Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

Focal and Segmental Glomerulosclerosis

Focal and segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases to terminate in ESRD. A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR) have not been defined. This study evaluated the rate of renal function decline (slope of creatinine clearance) and renal survival in nephrotic FSGS patients with CR, PR, or no remission. It also examined relapse rate from remission and its impact on outcome. Multivariate analysis included clinical and laboratory data at presentation and over follow-up, BP control, the agents used, and immunosuppressive therapy. The study cohort was 281 nephrotic FSGS patients who had a minimum of 12 mo of observation and were identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 65 mo, 55 experienced a CR, 117 had a PR, and 109 had no remission. A PR was independently predictive of slope and survival from renal failure by multivariate analysis (adjusted time-dependent hazard ratio, 0.48; 95% confidence interval, 0.24 to 0.96; P = 0.04). Immunosuppression with high-dose prednisone was associated with a higher rate of PR and CR. Relapse from PR was frequent (56%) and associated with a more rapid rate of renal function decline and worse renal survival compared with relapse-free partial remitters. Only female gender and the nadir of proteinuria during remission were associated with a sustained remission. A PR in proteinuria and its maintenance are important therapeutic targets in FSGS, with implications for both slowing progression rate and improving renal survival.

Molecular Analysis of NPHS2 and ACTN4 Genes in a Series of 33 Italian Patients Affected by Adult-Onset Nonfamilial Focal Segmental Glomerulosclerosis

Background: Mutations in the NPHS2 gene, encoding podocin, and in the ACTN4 gene, encoding α-actinin-4, have been identified in familial childhood-onset forms of focal and segmental glomerulosclerosis (FSGS). NPHS2 may be also responsible for some sporadic cases. The role of NPHS2 and ACTN4 in the adult sporadic form of the disease is being clarifying. Methods: Thirty-three adult subjects affected by sporadic FSGS were studied at molecular level. At biopsy, 12 patients had nephrotic syndrome, 5 patients had isolated proteinuria and 16 patients showed proteinuria and hematuria. Glomerular filtration rate (GFR) was in the normal range in 19 subjects and 14 patients had a variable degree of renal failure. Multiplex families presenting with a clear familial inheritance for proteinuria or other congenital nephrotic syndrome were excluded. The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects. Results: The analysis identified four already described and two new polymorphisms, IVS3–21C>T and IVS3–46C>T, on the NPHS2 gene. Moreover, the R229Q allele was identified in 3/33 patients and in 7/124 controls, accounting for an allelic frequency of 0.045 and 0.028, respectively. The new intronic polymorphism IVS7–54C>T was also found in the exon 8 of the ACTN4 gene. Conclusions: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic ‘adult-onset’ FSGS patients. No causative mutations were found while the R229Q allele was identified in 3 patients confirming its possible role as a ‘disease-associated NPHS2 allele’ although its pathogenetic involvement needs to be further clarified. Moreover, the description of new intronic polymorphisms in both genes is reported.

THE REMISSION OF FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS AFTER KIDNEY TRANSPLANTATION IN HUMANS IS ASSOCIATED WITH AN INCREASE IN PERIPHERAL T CD8+CD28-LYMPHOCYTES

P1025 Aims: Focal and Segmental Glomerulosclerosis (FSGS) is a glomerulopathy which recurs immediately after kidney transplantation (KTx) in 30 to 50% of patients, suggesting the involvement of systemic albuminuric factors. There is no identified links between such blood factors (or cells) and the immune system but some observations support a T cell origin. Methods: First, to demonstrate a potential implication of T lymphocyte in the relapse of FSGS, we investigated peripheral T cell selection and expansion before and after transplantation. PBMC were collected on the day and after KTx in 13 FSGS patients: 7 with recurrence (R, 4F, 3M) and 6 without (NR, 4F, 2M). Quantitative TCR repertoire analysis (TcLandscape) was performed at the level of Complementary Determining Region 3-Length Distribution (CDR3-LD). Second, to better characterize the T cell populations involved, we analyzed by flow cytometry the phenotype of peripheral T lymphocytes after Tx in 20 FSGS patients:10 NR patients (6F, 4M) and 10 R patients (6F, 4M). Six transplanted patients with chronic rejection (CR, 3F, 3M) were considered as a control group of R patients (proteinuria matched). All groups were matched for age, sex and treatment. Non parametric test was performed and P values < 0.05 were considered significant. Results: NR patients displayed significantly more CDR3-LD alterations than R patients before and after transplantation (25±1.3% vs. 18.1±1.9%, p=0.03 and 26.1±4.2% vs. 17.7±1%, p=0.02 respectively). After Tx, in comparison with NR patients, R and RC patients had a significant increase in their CD8+CD28+ T cells (76.9±4.1% and 75±3.8% vs. 59.7±5.75%, p=0.03 and p=0.04) and CD8+CD25+ T cells (9.75±1.4% and 12.3±1.6% vs. 5.5±0.7%, p=0.009 and p=0.002). Patients without recurrence had more CD8+CD28- T lymphocytes (40.3±5.7% vs. 23.1±4.1%(R) and 25±3.8% (CR), p=0.02 and p=0.04), which are known to be potentially T suppressor cells. No difference was observed between the different groups for the CD4+ T cell phenotype. Conclusion: Non recurrent patients present significant alterations of their TCR usage. Peripheral CD8+ T lymphocytes may play a role in the evolution of patients with FSGS after KTx. Recurrence is associated with an increase in CD8+CD25+ and CD8+CD28+ T cells while non recurrence present more CD8+CD28- cells.

NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.

Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro-translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.

NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele

Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro–translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation

Several families have been described in which an A to G transition mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined. Among 11 biopsy-proven primary FSGS patients of unknown etiology, we examined seven FSGS patients to determine whether any of the clinical and pathological features of FSGS were associated with an A3243G mtDNA mutation. In four subjects in whom the A3243G mtDNA mutation was discovered in blood leukocytes, as well as in urine sediments, we retrospectively reviewed the medical records and re-evaluated the renal biopsy specimen using light and electron microscopy. We further screened the patient's family members for the presence and degree of heteroplasmy for this mtDNA mutation and obtained medical histories that were consistent with mitochondrial cytopathy. The four individuals identified with the A3243G mtDNA mutation were female. Proteinuria was diagnosed in these individuals during a routine annual health checkup in their teenage years. None of the patients showed any symptoms related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode, whereas diabetes mellitus in two of the patients and a hearing disturbance in one patient became manifest within a 3- to 13-year follow-up period. Strict maternal transmitted inheritance was confirmed by pedigree studies in all of these patients. Steroid therapy was ineffective in all four patients. In two of these patients, renal function declined slowly to end-stage renal failure. Histologic examination of biopsy specimens revealed that glomeruli were not hypertrophied, while electron microscopic examination identified severely damaged, multinucleated podocytes containing extremely dysmorphic abnormal mitochondria in all patients. FSGS may belong to the spectrum of renal involvement in A3243G mtDNA mutation in humans. Severely injured podocytic changes containing abnormal mitochondria may explain the pathogenesis of FSGS in association with the A3243G mtDNA mutation.

Two Different Pathways of Glomerular Enlargement in Adults with Focal and Segmental Glomerulosclerosis: A Morphometric Study

The renal biopsy specimens obtained from 15 adults with focal and segmental glomerulosclerosis (FSGS) and 15 adults with minimal change nephrotic syndrome (MCNS) were morphometrically analyzed using light and electron microscopy. Moreover, initial biopsy specimens obtained from 10 adults who were diagnosed as MCNS and developed FSGS, based on repeat biopsy findings (‘MCNS’-FSGS), were also analyzed using electron microscopy. After comparing the actual values between the groups of FSGS and MCNS, the mean glomerular volume, the capillary volume per a glomerulus, the capillary filtration surface per a glomerulus, and the capillary diameter (Cap-D) were all larger in the FSGS group than in the MCNS group. In regard to the morphological values in the ‘MCNS’-FSGS group, both values of the surface density of the capillary filtering surface and the capillary diameter at the first biopsy specimens as well as those in the FSGS group were higher than those in the MCNS group. When analyzing the structural parameters, in the FSGS series, we found a high association of the percentage of obsolescent glomeruli (%SG) with the mean glomerular volume, the capillary volume per a glomerulus, the capillary filtering surface per a glomerulus and the capillary length per a glomerulus, however we failed to demonstrate the correlation between the %SG and the Cap-D. Thus, the glomerular structure in the ‘MCNS’-FSGS patients, even at the first renal biopsy, resembled that in FSGS, suggesting FSGS to be a distinct entity from MCNS. These data indicate that the enlargement of the capillary volume, resulting from the widening of the capillaries, was the initial structural event for adults with FSGS, while the elongation of the capillaries appeared to reflect some compensatory process for the decrease in the functioning nephron.

HLA Associations in IgA Nephropathy and Focal and Segmental Glomerulosclerosis

Twenty percent of patients initiating Medicare-supported end-stage renal disease (ESRD) therapy in the United States have chronic glomerulonephritis-induced ESRD. IgA nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS) likely account for many of these incident dialysis cases, although patients presenting with advanced renal insufficiency may not receive renal biopsies. To determine whether HLA phenotype associations existed in the subset of IgAN and FSGS patients who develop ESRD, we analyzed HLA frequencies by race in patients with these etiologies of ESRD entered in the South Eastern Organ Procurement Foundation (SEOPF) database. Serologically determined HLA frequencies from 605 renal transplant recipients with ESRD due to FSGS and 196 renal transplant recipients with ESRD due to IgAN were compared with those of 4,506 race-matched cadaveric kidney-donor controls. Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between the HLA system and ESRD due to IgAN and FSGS. Values reported were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-B27 and HLA-DR1 frequencies were increased and HLA-DR2 frequency was decreased in African-American and white IgAN-induced ESRD cases compared with race-matched controls (race-combined OR of 2.10, 1.89, and 0.57, respectively; all P < or = 0.004). HLA frequency differences were not observed in FSGS-induced ESRD patients compared with controls. The results of this study indicate that HLA-B27 and HLA-DR1 are positively associated and HLA-DR2 is negatively associated with IgAN-induced ESRD in patients of both races.(ABSTRACT TRUNCATED AT 250 WORDS)